Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain, which is characterized by the memory deterioration, behavioral disturbances, impairment of activities of daily living, and loss of independent function. It is thought that 18-24 million people in the world are currently suffering from AD, two-thirds of whom are living in developed or developing countries. This number is expected to reach 34 million by 2025.
Accumulation of insoluble aggregates of amyloid-beta peptide (Aβ) is thought to be a central mechanism for the pathogenesis of AD. Aβ peptides are generated from the cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases. Cleavage of APP by BACE1 (Beta Amyloid Cleaving Enzyme-1) is believed to be a prerequisite for gamma-secretase-mediated processing.
A number of drugs aimed at inhibiting the accumulation of Aβ have failed in clinical trials. Other drugs that are still in clinical trials are also directed at inhibiting the accumulation of Aβ. However, most experts now believe that it may be too late to start Aβ inhibitory therapies after a patients shows symptoms.
For example, a mutant allele of the tau protein was targeted in vitro using shRNA plasmids, demonstrating that a single nucleotide mutation could be used to suppress mutant tau by siRNA. Dominantly inherited mutations in the tau gene may be targets in neurodegenerative diseases other than AD. Frontotemporal dementia with parkinsonism linked to chromosome 17 has mutations in tau, resulting in altered sequence or aberrant splicing. Abnormal expression of tau is also associated with progressive supranuclear palsy and corticobasal ganglionic degeneration.
Additional targets for AD include the apolipoprotein E ε4 allele (ApoE4), the secretases, and the presenilin genes. Together with increasing age, ApoE4 is considered the most significant risk factor for AD. Suppression of ApoE4 with siRNA could potentially reduce the probability of developing AD or delay its onset, at least in heterozygotes. Because ApoE4 plays a critical role in cholesterol and triglyceride transport, the risk-benefit ratio of gene targeting in ApoE4 homozygotes is less clear. More than 150 mutations have been identified in the presenilin genes, which result in an early-onset aggressive form of AD. Presenilin is the catalytic subunit of γ-secretase, and the mutations in presenilin enhance production of the highly self-aggregating Aβ42 peptide, which can be reversed by suppressing mutant presenilin with siRNA. This leads to the question of whether the secretases could be the point of therapeutic intervention. Because β-secretase-deficient mice have no apparent deficits, this particular enzyme may be a good therapeutic target.
Accordingly, therapies directed to inhibiting tau proteins or other proteins involved in the process are gaining more attention. Under normal circumstances, tau helps build the microtubule structures in neurons. However in diseased brains, this long protein with more than 400 amino acids, misfolds and aggregates into tangles within neurons. Higher levels of tau in the cerebrospinal fluid are associated with advancing AD. It is thought that extracellular tau isn't detritus shed by dead neurons, but rather material secreted by diseased neurons, which acts as a disease transport, shuttling from neuron to neuron along the synapses and triggering more misfolding, more tangles and more neurotoxicity.
New therapies for Alzheimer's are needed.